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Disease Profile

Klinefelter syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

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ICD-10

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Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Klinefelter's syndrome; XXY syndrome; 47,XXY syndrome;

Categories

Congenital and Genetic Diseases

Summary

Klinefelter syndrome (KS) is a condition that occurs in males when they have an extra X chromosome. Some males with KS have no obvious signs or symptoms while others may have varying degrees of cognitive, social, behavioral, and learning difficulties. Adults with Klinefelter syndrome may also have primary hypogonadism (decreased testosterone production), small and/or undescendent testes (cryptorchidism), enlarged breast tissue (gynecomastia), tall stature, and/or inability to have biological children (infertility), as well as an abnormal opening of the penis (hypospadias), and an small penis (micropenis). KS is not inherited, but usually occurs as a random event during the formation of reproductive cells (eggs and sperm) that results in the presence of one extra copy of the X chromosome in each cell (47,XXY). KS treatment is based on the signs and symptoms present in each person.[1][2][3] Life expectancy is usually normal and many people with KS have normal life. There is a very small risk of developing breast cancer and other conditions such as a chronic inflammatory disease called systemic lupus erythematosus.[3] 

In some cases, there is more than one X chromosome in each cell (for example, 48,XXXY or 49,XXXXY). These conditions, which are often called "variants of Klinefelter" syndrome usually have more serious problems (intellectual disability, skeletal problems, and poor coordination) than classic Klinefelter syndrome (47,XXY).[3]

Symptoms

The signs and symptoms of Klinefelter syndrome (KS) vary among affected people. Some men with KS have no symptoms of the condition or are only mildy affected. In these cases, they may not even know that they are affected by KS. When present, symptoms may include:[1][2][3]

  • Small, firm testicles
  • Delayed or incomplete puberty with lack of secondary sexual characteristics resulting in sparse facial, body, or sexual hair a high-pitched voice and body fat distribution resulting in a rounder, lower half of the body, with more fat deposited in the hips, buttocks and thigh instead of around the chest and abdomen
  • Breast growth (gynecomastia)
  • Reduced facial and body hair
  • Infertility
  • Tall stature
  • Abnormal body proportions (long legs, short trunk, shoulder equal to hip size)
  • Learning disability
  • Speech delay
  • Crypthochirdism
  • Opening (meatus) of the urethra (the tube that carries urine and sperm through the penis to the outside) on the underside of the penis (hypospadias) instead of the tip of the head of the penis
  • Social, psychologic and behavioral problems

Whether or not a male with KS has visible symptoms depends on many factors, including how much testosterone his body makes, if he is mosaic (with both XY and XXY cells), and his age when the condition is diagnosed and treated.[1] Some people have a slightly increased risk of developing breast cancer, a rare extragonadal germ cell tumor, lung disease, varicose veins and osteoporosis as well as some autoimmune disorders such as systemic lupus erythematosus, rheumatoid arthritis and Sjogren's syndrome.[2][4] 

Some people with features of Klinefelter syndrome have more than one extra X chromosome in each cell (such as 48,XXXY or 49,XXXXY). In these cases, known as "variants of Klinefelter syndrome", the signs and symptoms can be more severe and may include:[1][2][4]

  • Intellectual disability
  • Distinctive facial features
  • Skeletal abnormalities
  • Poor coordination
  • Severe speech difficulties
  • Behavioral problems
  • Heart defects
  • Teeth problems.

Cause

Klinefelter syndrome usually occurs as a random event during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in a reproductive cell with an abnormal number of chromosomes. For example, an egg or sperm cell may gain one or more extra copies of the X chromosome as a result of nondisjunction. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have one or more extra X chromosomes in each of the body's cells.[2]

Most often, Klinefelter syndrome is caused by a single extra copy of the X chromosome, resulting in a total of 47 chromosomes per cell. Males normally have one X chromosome and one Y chromosome in each cell (46, XY), while females have two X chromosomes (46, XX). People with Klinefelter syndrome usually have two X chromosomes and one Y chromosome (47, XXY). Some people with Klinefelter syndrome have the extra X chromosome in only some of their cells; these people are said to have mosaic Klinefelter syndrome.[2]

It is estimated that about half of the time, the cell division error occurs during development of the sperm, while the remainder are due to errors in egg development. Women who have pregnancies after age 35 have a slightly increased chance of having offspring with this syndrome.[5]

The features of Klinefelter syndrome are due to the extra copies of genes on the extra X chromosome, which can alter male sexual development.[3]

Some people with features of Klinefelter syndrome have conditions known as "variants of Klinefelter syndrome" where there is more than one extra sex chromosome in each cell (48,XXXY, 48,XXYY and 49,XXXXY).[5]

Diagnosis

A diagnosis of Klinefelter syndrome is often suspected based on the presence of characteristic signs and symptoms. Additional testing can then be ordered to confirm the diagnosis. This generally includes a chromosomal analysis (called a karyotype).[3][6] 

It is also possible to diagnosis Klinefelter syndrome before birth through chorionic villous sampling or amniocentesis.[6]

Treatment

Because symptoms of Klinefelter syndrome (KS) can sometimes be very mild, many people are never diagnosed or treated. When a diagnosis is made, treatment is based on the signs and symptoms present in each person, especially the problems related to hypogonadism, gynecomastia, and psychosocial problems. Treatment may include:[1][3][4]

  • Testosterone replacement: About half of people with SK have low testosterone levels, which may be raised by taking supplemental testosterone. Having a more normal testosterone level can help affected people develop bigger muscles, a deeper voice, and facial and body hair, and may also increase sexual desire, enlarge the testes, improve mood, self-image, and behavior; it may also protect against osteoporosis and decrease the risks of autoimmune disease and breast cancer.
  • Breast removal or reduction surgery.
  • Educational interventions: As children, many people with Klinefelter syndrome qualify for special services to help them in school. Teachers can also help by using certain methods in the classroom, such as breaking bigger tasks into small steps.
  • Several forms of therapy such as physical, speech, occupational, behavioral, mental health, and family therapy can often help reduce or eliminate some of the symptoms of Klinefelter syndrome such as poor muscle tone; speech and language problems; or low self-confidence.

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

    • The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provides information related to the health of children, adults, and families. Click on the link to view information on this topic.
    • MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
    • MedlinePlus Genetics contains information on Klinefelter syndrome. This website is maintained by the National Library of Medicine.
    • The National Human Genome Research Institute's (NHGRI) website has an information page on this topic. NHGRI is part of the National Institutes of Health and supports research on the structure and function of the human genome and its role in health and disease.
    • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

      In-Depth Information

      • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss Klinefelter syndrome. Click on the link to view a sample search on this topic.

        References

        1. Klinefelter syndrome. Eunice Kennedy Shriver National Institute of Child Health and Human Development. November 2013; https://www.nichd.nih.gov/health/topics/klinefelter/Pages/default.aspx.
        2. Klinefelter syndrome. Genetics Home Reference. January 2013; https://ghr.nlm.nih.gov/condition=klinefeltersyndrome.
        3. Kirmse B. Klinefelter syndrome. MedlinePlus. November 2014; https://www.nlm.nih.gov/medlineplus/ency/article/000382.htm.
        4. Chen H. Klinefelter syndrome. Medscape Reference. 2018; https://emedicine.medscape.com/article/945649-overview.
        5. Learning about Klinefelter syndrome. National Human Genome Research Institute. October 2011; https://www.genome.gov/19519068.
        6. Klinefelter Syndrome. National Organization for Rare Disorders. 2014; https://rarediseases.org/rare-diseases/klinefelter-syndrome/.
        7. Klinefelter syndrome. Genetics Home Reference (GHR). January 2013; https://ghr.nlm.nih.gov/condition/klinefelter-syndrome. Accessed 4/14/2015.

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